NAMHC Minutes of the 236th Meeting

January 23, 2014

Department of Health and Human Services Public Health Service National Institutes of Health National Institute of Mental Health

Introduction

The National Advisory Mental Health Council (NAMHC) convened its 236th meeting in open policy session at approximately 9:30 a.m. on January 23, 2014, in the Neuroscience Center in Rockville, Maryland, and adjourned at approximately 2:20 p.m. In accordance with Public Law 92-463, the policy session was open to the public. The NAMHC reconvened for a closed session to review grant applications at approximately 3:00 p.m. on January 23, 2014, at the Neuroscience Center in Rockville, MD, until adjournment at approximately 5:00 p.m. (See Appendix A: Review of Applications). Thomas Insel, M.D., Director, National Institute of Mental Health (NIMH), presided via videoconference until noon, after which time Philip Wang, M.D., Dr. P.H., NIMH Deputy Director, presided.

Open Policy Session Call to Order and Opening Remarks

NIMH Director Thomas Insel, M.D. called the open policy session to order and welcomed all in attendance.

Approval of Minutes of the Previous Council Meeting

Turning to the minutes of the September 19, 2013, Council meeting, Dr. Insel asked if Council members had any comments, revisions, or questions about the minutes. Receiving none, the motion to approve the minutes was unanimously passed.

NIMH Director’s Report

Dr. Insel began his Director’s Report by congratulating Tom Südhof, M.D., an NIMH grantee, for sharing in the 2013 Nobel Prize in Physiology and Medicine. He also noted that of Science magazine’s top 10 breakthroughs of 2013, NIMH can claim partial ownership of four: Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), three-dimensional postmortem anatomical analysis, Clear Lipid-exchanged Anatomically Rigid Imaging/Immunostaining-compatible Tissue hYdrogel (CLARITY), the effects of sleep on storage and processing of information, and the development of organoids. In addition, Nature Biotechnology announced single-cell sequencing as the method of the year, a Common Fund project co-led by NIMH’s Andrea Beckel-Mitchener, Ph.D.

Dr. Insel spoke about the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) initiative, announced by President Obama on April 2, 2013. The National Institutes of Health (NIH) BRAIN Working Group, an advisory group to the NIH Director, has provided an interim report, which led to the release of a series of Request for Applications (RFA) in December 2013, of which NIMH is responsible for three (of six). A final report from the working group is expected in June 2014.

In looking to the challenges ahead, Dr. Insel cited the Global Burden of Disease study, which tracks 291 diseases and injuries across 187 countries to calculate the impact of disease on morbidity and mortality. In 2010, neuropsychiatric disorders comprise the largest single source of disability-adjusted life years (DALYs) and are by far the largest source of years of life lost to a medical cause (18.7 percent). Mental and behavioral disorders make up 13.6 percent of DALYs, of which major depressive disorders is the greatest percentage (27.37 percent), followed by drug use (19.18 percent), anxiety disorders (18.75 percent), alcohol use (10.28 percent), schizophrenia (7.5 percent), and bipolar disorder (5.19 percent). Compared to HIV/AIDS, which fell from 11 to 33 on the DALYs list, the mental and behavioral disorders have held steady or actually moved up on the list. This shift illustrates the benefits that have been gained by investment in HIV/AIDS research and highlights the importance of strategic investment in mental health research.

Referencing Peter Medawar’s statement that “Science is the art of the soluble,” Dr. Insel described a meeting with the Gates Foundation, which subscribes to the philosophy of “Dollars for DALYs”—that is, finding a problem that is easily and inexpensively solved. He urged the Council to think about how best to invest NIMH funds from discovery to delivery and to consider how, who, and what in supporting the best science.

In thinking about how to select the best science for funding, one issue to consider is peer review—whether it is responsive to the science and of equal quality across study sections. NIMH and other NIH Institute and Centers (ICs) are in the process of analyzing massive amounts of data to try to develop predictors of successful science. A recent study by Michael Lauer, M.D. of the National Heart, Lung, and Blood Institute published in Circulation Research found little correlation between the percentile ranks of applications and one measure of quality (citations) corrected for the size of the award. A recent NIH leadership retreat discussion centered on the idea that percentiles are not comparable across study sections, that study sections provide one assessment of merit within a broad range (taking 50 to 60 percent of grants off the table), and that a second tier of review from program staff and Council can refine assessment. Generally speaking, one can assume that everything under the 20th percentile would likely be considered a meritorious application. However, NIMH does not adhere to a strict payline; rather, it endeavors to fund 75 percent of the grants under the 20th percentile, ranked by public health need, portfolio balance, and the quality of the science. Thus, some grants below the 10th percentile might not be funded. The Institute relies heavily on two tiers of review.

A second issue to consider is the balance between investigator-initiated grants and requests for applications (RFAs) which can direct funds to an underfunded area for which few applications are being submitted. The balance between unsolicited and solicited applications may depend on the state of the science. Different considerations might apply to research depending on whether it is at the discovery end of the pipeline versus the delivery end, where there might be a greater need for direction and attention to DALYs through RFAs. These considerations map onto the divisional structure of NIMH, from the Division of Neuroscience and Basic Behavioral Science (DNBBS) at the discovery end, to the Division of Services and Intervention Research (DSIR) at the delivery end of the pipeline. In the past few years, NIMH has increased the amount of its targeted funding from 20 to 30 percent as a way to attract scientists to the areas critical to its mission. Dr. Insel asked Council for its input on these issues.

On the topic of whom NIMH supports, Dr. Insel mentioned the difference between programs that fund the idea (e.g., R01s) versus those that fund the individual (e.g., Division of Intramural Research Programs [IRP], NIH Pioneer Awards). A persistent and growing concern across NIH is the fate of young investigators—the mean age of receipt of a first R01 is 42 years. One question is whether more, smaller awards over a shorter time period would benefit this population. Finally, if a smaller group of individuals makes a disproportionate number of breakthroughs, can these few people be supported earlier and longer? Dr. Insel used the example of 32-year-old Feng Zhang, who developed CRISPR, to highlight the importance of Pioneer Awards for high-risk, high-reward investments. The NIH system increasingly awards more funds to scientists over age 66 than under age 36.

NIMH has developed the BRAINS Program (Biobehavioral Research Awards for Innovative New Scientists), which solicits highly innovative and ambitious research applications from early-stage investigators that address a critical knowledge gap identified in the NIMH Strategic Plan. Awardees receive five years of support, up to $1.6 million. Since 2009, 135 applications have been received with 38 awards (28 percent success rate).

Budget Update

The fiscal year (FY) 2014 Omnibus budget provides NIH with $30.15 billion. This is a $1 billion increase over FY 2013, but still lower than the FY 2012 budget by $0.71 billion. There are specific increases for Alzheimer’s disease research ($100 million) and a shift of $45 million from Common Fund programs to National Center for Advancing Translational Sciences (NCATS) and $22 million to the BRAIN initiative. The budget provides a general increase for NIH ICs of 3 percent over FY 2013. The FY 2013 success rate for NIMH was 19 percent (512 new and competing grants funded out of 2,600 applications). NIMH would like to push the rate above 20 percent and hopes to fund 550 grants in FY 2014. In total, NIMH’s budget is approximately $1.4 billion, of which non-competing awards comprise $630 million, potentially 590 new competing awards comprise $236 million, and new funding comprises $9.75 million through the BRAIN initiative. Of note, the SAMHSA appropriation requires coordination with NIMH to incorporate knowledge gained from the RAISE (Recovery After Initial Schizophrenia Episode) initiative into block grants.

Discussion

Deanna Barch, Ph.D., asked whether reliance on program staff and Council for funding decisions has implications for the selection and evaluation process. Dr. Insel responded that the Institute has made a concerted effort to bring in staff with deep understanding of the science that can provide the needed expertise, supplemented by Council’s depth and breadth. Steven E. Hyman, M.D., commented that it is always challenging to organize study sections so they remain relevant and do not become entrenched in a way that is damaging to innovation. He agreed with NIMH’s policy to avoid adherence to paylines as a policy for making funding decisions. Dr. Insel noted that Richard Nakamura, Ph.D., formerly of NIMH, is now head of the Center for Scientific Review and has thought deeply about the peer review system. The key is remaining flexible and renewable. Beatriz Luna, Ph.D., said that it is important to support the people who drive the science to innovation as well as the innovators. Dr. Insel agreed and added that it is important to reserve a certain percentage of funds to support people instead of projects. He asked for Council’s help in finding the right balance.

Nancy Kanwisher, Ph.D., asked if NIMH has analyzed its own study sections and whether an impact can be found from funding decisions. Dr. Insel responded that NIMH has begun this process, but one challenge is determining what constitutes impact. Informally, programs have been asked to name areas where there has been a breakthrough and then “reverse engineer” the results to see whether NIH or NIMH funding was involved and, if so, determine the score received in review. One finding has been that some of the most important science has also been the most expensive.

Edwin Abel, Ph.D., asked if NIMH has considered other means for bringing outside expertise as program staff, similar to the system used by the National Science Foundation (NSF) or the Defense Advanced Research Projects Agency (DARPA). Dr. Insel replied that the NSF model is undergoing scrutiny right now, but NIMH uses a DARPA-like model in managing its contracts. NIH has certain constraints that prevent full adoption of the DARPA model of project management.

Marsha M. Linehan, Ph.D., encouraged NIMH to develop ways to mentor young investigators, citing the beneficial influence that site visits had on her own career. Although Dr. Insel agreed with the need to help young investigators navigate the review process, site visits are difficult because of government-wide travel restrictions.

NIMH Strategic Planning

Kevin Quinn, Ph.D., Acting Director, Office of Science Policy, Planning, and Communications (OSPPC), opened his presentation by stating that the NIMH Strategic Plan is now more than 5 years old and although still valid, needs updating. He described the 2008 Plan structure and Strategic Research Priorities. As the update to the Strategic Plan continues, NIMH will request Council input, and the updated Plan will be posted for public comment.

Brent Miller, Ph.D., of OSPPC, introduced the four Strategic Objectives of the 2008 Plan: (1) promote discovery in the brain, (2) chart mental illness trajectories, (3) develop new and better interventions, and (4) strengthen the public health impact of NIMH-supported research. Within each broad objective are more detailed strategic research priorities. The Plan provides a solid foundation for the current effort. However, changes in the landscape require updating the research priorities.

Dr. Miller highlighted some of the progress made recently (e.g., the Research Domain Criteria (RDoC) project, the RAISE initiative). New opportunities and challenges lie ahead, such as the Early Prediction and Prevention of Psychoses initiative, the National Research Action Plan, and the BRAIN initiative. Three guiding principles underlie efforts to update the Plan for 2014: (1) produce a vision-level document supplemented by nimble strategic research priorities; (2) emphasize progress made and the future potential of NIMH activities; and, (3) refresh rather than rewrite the 2008 Plan.

To initiate the planning process, the strategic research priorities were reviewed and revised through a survey of Program staff. The preliminarily revisions will be discussed within NIMH, and these edited strategic research priorities will be used as a foundation for updating the vision-level strategic plan. Council was asked to provide input on high-level priorities, which were collected and collated prior to this meeting.

Dr. Quinn discussed the major themes provided by Council in advance of the meeting. He noted that two issues emerged from the 2008 Plan that remain relevant today: psychiatric diagnosis and the relationship to what we are learning about the brain, and the need for data sharing to accelerate research. NIMH has taken these concerns seriously, as evidenced by RDoC, the National Database for Autism Research, and the Psychiatric Genetics Consortium.

Randall Carpenter, M.D., urged thinking broadly about one of the strategic research priorities under Strategic Objective 1: “Develop next-generation neuromodulation technologies that leverage new advances in engineering and chemistry.” Rather than targeting therapeutics at the individual molecule, the scientific community needs tools and incentives to go after networks as therapeutic targets. J. David Sweatt, Ph.D., added that this priority is linked to another: “Increase the ability of the scientific community to collect, deposit, and use ‘big data’ in real time, as well as use it more broadly.” He said that next generation sequencing will enable genomic circuit-level analyses of interactions in an experimental fashion, which will facilitate network-level analyses. A question is whether every IC will have to develop the bioinformatics capability and computational biology infrastructure.

Sarah Lisanby, M.D., agreed that we need to understand multi-focal targeting and assess complex systems across the levels of analysis. The emphasis is not just on a distributed network in discrete brain areas, but also on drilling down into individual cell types and within cells at the RNA and DNA levels. New developments in nanotechnology will facilitate analysis across multiple levels.

B.J. Casey, Ph.D., said that the use of mobile technologies for detection, intervention, and treatment of mental disorders will rest on the capacity to collect and use big data in real time. Dr. Lisanby added that mobile technologies could track social interaction and environmental exposures to complement data collected on biomarkers. Patricia A. Areán, Ph.D., added that mobile technologies could be used for interventions that involve the use of cognitive training games tailored to specific populations. Efforts should center on mobile detection and mobile treatment and the deposit of such data into large repositories for research use.

Gregory E. Simon, M.D., M.P.H., also commented on big data, asking how to best engineer the system so that vertically and horizontally integrated data are accessible for research purposes.

Gene Robinson, Ph.D., said that we are on the verge of documenting the fact that different neurons potentially have different genomes, which requires a big data approach if we are to elucidate new disease models, threshold effects, the collective activities of neurons, and discern signals from background noise.

Dr. Carpenter said that lessons can be learned from breast cancer and HIV, in which compounds were studied in humans, and findings were mixed with ‘big data’ in the form of genetics, behavioral factors, and economic and environmental factors. This combined approach led to the understanding of the variations in response to treatment and moved subsequent advances in therapy.

Dr. Abel encouraged using RDoC strategically to design more intelligent clinical trials. He added that current animal models are not modeling disease; thus, greater efforts are needed to connect animal models to disease through examining variations and the structure of neural circuits. In addition, the brain is unique with regard to epigenetic modifications, which must be considered in pharmacological studies.

Mary Jane Rotheram, Ph.D., questioned how NIMH intends to achieve balance between basic science and mental health across the four Strategic Objectives. She said that mental health is not merely a brain disorder and questioned that emphasis in the Strategic Objectives of the Plan.

Dr. Barch encouraged NIMH to pay attention to common risk factors for many disorders beyond genetics to include family environment, paternal support, poverty, nutrition early in life, and exposure to toxicity early in life. Such an environmental focus may inform early intervention and prevention. She opined that a greater understanding of the mechanisms by which some of these common risk factors confer risk is needed. Dr. Simon agreed that the field needs to move beyond the simplistic linking of risk factors to outcomes and understand the mechanistic pathways and why risk factors do not affect everyone equally.

Kerry Ressler, M.D., Ph.D. advocated a focus on the neurobiology of aggression and prevention of aggression and violence. He added that he would like to see something in the Plan that uses induced pluripotent cell lines for whole genome sequencing.

David A. Brent, M.D., said that there are common risk factors for both cardiovascular disease and depression, but the ICs are not organized to support research that could reduce leading causes of disability worldwide. He said that he has concerns about our ability to analyze big data and recommends reaching out to mathematicians for assistance.

Dr. Linehan said that we need to understand how behavior and therapy changes the brain. We know that some treatments work, but we don’t always know why; we need studies that reveal how the brain responds to these interventions and why some treatments are effective for some but not all.

Dr. Hyman asked whether privacy protections might make it difficult to recruit people into some types of studies. Regarding data, he cautioned that not all data are good, and some were obtained using older, less accurate methods. Greater efforts are needed to interrogate the complexity in genetics and epigenetics rather than focusing primarily on the main effects or specific genes.

Dr. Lisanby noted that practicing psychiatrists routinely ask people for subjective reports about how they are feeling, when there are actually methods to quantify their moods, behavior, and social interactions that could be captured using mobile technology. In addition, vast amounts of information exist in medical records that can be mined to match patients with patterns of clinical presentations. Thus, we need to improve methods for data mining while being mindful of privacy concerns.

Richard L. Huganir, Ph.D., urged holistic consideration of how the body can control brain development and brain function. Although some brain disorders change behavior, the reverse is also true. Anissa Abi-Dargham, M.D., said that the rapidly developing fields of genetics, cell biology, and neuroscience, among others, highlight the need for cross-training clinicians in some area of science and basic researchers in clinical settings—in other words, more translational centers.

Carol Tamminga, M.D., stressed the need for better models with a specific focus on psychiatry, saying that the field does not do a good job of defining diseases and should direct its focus on translation. Dr. Carpenter added that the field should embrace the heterogeneity found across populations and work to understand the factors that are associated with beneficial and non-beneficial treatment outcomes among individuals.

Matthew State, M.D., Ph.D., said that the Strategic Plan should include funding mechanisms for resources (e.g., computational biology or mobile technology). Dr. Rotheram agreed that NIMH should help establish big data infrastructure and leverage access to existing large datasets.

Dr. Kanwisher emphasized the importance of collecting data from large population samples to better understand variability within and outside the norm. Obtaining simple behavioral measures over the Internet has dramatically advanced the field of cognitive science because of real-time access to large samples.

Dr. Insel closed the session by saying that staff will distill the comments and possibly request additional input from Council. Because ‘big data’ is a large component of the Common Fund, NIMH will be exploring how best to leverage the NIH investment.

Grayson Norquist, M.D., M.S.P.H., Chair, Patient-Centered Outcomes Research Institute (PCORI) Board of Governors described the origins of PCORI, its legislative mandate through the Patient 9 Protection and Affordable Care Act, its initial operations, and its three strategic goals:

increase quantity, quality, and timeliness of research information;

expedite the implementation and use of evidence; and

influence research funded by others.

The Board of Governors, whose membership representation is dictated by statute to include a wide range of stakeholders, organizes its activities around the strategic goals.

Dr. Norquist welcomed the opportunity to consider how PCORI might co-fund projects with NIMH. He discussed his experiences practicing in the Mississippi Delta after leaving his position at NIMH, where he gained a greater appreciation of the types of problems with which people in underserved areas experience. It also helped him appreciate the need for a patient focus in clinical care. He emphasized that PCORI’s mandate is broader than conducting comparative-effectiveness research, although that is a centerpiece of its activities. It also has a mandate to study rare diseases.

The legislation requires PCORI to establish a standing methodology committee for comparative clinical effectiveness research. This committee recently issued a report on how to conduct patient-centered outcomes research. It also has provided input to the PCORI review process, which includes consumers as stakeholders. Patient/consumer perspectives are important in understanding the importance of quality of life as well as the effectiveness of a given therapy. Thus, patients/consumers participate in merit review as well as in topic selection.

PCORI’s national priorities for research are as follows:

assessing prevention, diagnosis, and treatment options;

improving healthcare systems;

communicating and disseminating research;

addressing disparities; and

accelerating patient-centered research and methodological research.

PCORI has developed review criteria focused on impact on health, potential for improving care and outcomes, technical merit, patient-centeredness, and patient and stakeholder engagement. Funded research must adhere to 47 methodology standards. Cost cannot be a consideration in the review process.

PCORI is funded through two funding streams: the general fund of the Treasury, and a small fee assessed on Medicare, private health insurance, and self-insured plans. As of January 2014, 279 projects have been funded at a level of $464.4 million. Funded research is taking place in 37 States, as well as the District of Columbia.

Dr. Norquist described the PCORI research portfolio, much of which includes a behavioral or mental health focus:

50 awards totaling $31 million support projects that advance methods for engaging patients and other stakeholders in the research process;

30 awards totaling $28 million aim to accelerate patient-centered research and methods.

Other funding is available for large trials focused on specific topics, such as treatment options for African Americans and Latinos/Hispanics with uncontrolled asthma ($28 million).

The Eugene Washington Engagement Awards provide a small amount of funds to consumer/patient groups to work with researchers to develop proposals. The payline approximates the 15th percentile; however, decisions are based on a portfolio management approach. Extensive literature reviews are conducted on topics considered for funding.

Approximately $50 million has been awarded to 31 projects in mental health. Potential new projects include diagnosis and management of bipolar disorder in adolescents, use of antipsychotics in children, and integration of mental health into primary care. A funding announcement is being prepared asking for large pragmatic trials in areas of interest to PCORI.

In January 2014, PCORI announced the creation of the National Patient-Centered Clinical Research Network to conduct large-scale efficient comparative-effectiveness research. It is a system of networks (clinical research data and patient-powered, of which one is in mental health) with a coordinating center that provides assistance under the direction of a Steering Committee and PCORI staff. The mental health project aims to recruit 50,000 people with mood disorders into a network. These network platforms are available for everyone to use.

Discussion

Dr. Tamminga asked for examples of mental health studies supported by PCORI. Dr. Norquist described a study by Ken Wells looking at long-term outcomes of community engagement to address depression outcome disparities. PCORI is open to ideas as long as they are focused on effectiveness.

Dr. Linehan asked about patient engagement and whether patients with cognitive impairment would be able to provide useful input. Dr. Norquist said that patients are involved throughout the process. Dr. Hyman added that it helps recruitment and engagement to get patient input on study design. Dr. Sweatt said that it is particularly important to engage patients and families in the rare diseases because often they are the most expert about the disorder. However, there might not be a large patient population, which could make such engagement challenging. Dr. Norquist said PCORI has a Rare Disease Advisory Panel and is able to tap into international patient populations, which expands capacity.

In response to a question from Dr. Barch about whether PCORI is receiving mental health submissions, Dr. Norquist said that it is uneven across the topics and that the Institute is still developing its review process. Applicants can apply as many times as they wish.

Dr. Simon asked how PCORI is addressing the balance between average effects in large simple trials and the ability to personalize effects. Dr. Norquist said PCORI is optimistic that large trials might be able to address that issue, but the methods are still being developed. Dr. Carpenter asked how PCORI accounts for variations in preferences among patients since the 11 measurements and outcomes have to be patient-centered. Dr. Norquist, referring to “preference-omics,” said that PCORI is working on methods to understand the personalization of treatments. Dr. Hyman added that traditional randomized controlled trials only focus on symptom reduction, when trials should be measuring a variety of outcomes that people care about.

Maria A. Oquendo, M.D., suggested that PCORI encourage mental health to be part of any assessment since it is critical to many outcomes, including adherence. Dr. Norquist answered that the focus is on functional, patient-centered measures, which is not inconsistent.

Dr. Linehan asked whether uniform measures are being used. Dr. Norquist said that the network is being used to enhance uniformity.

Dr. Simon encouraged PCORI to also consider measuring and understanding the adverse effects of treatment from a patient perspective, to which Dr. Norquist agreed.

NIMH FAST Workgroup: Update on Activities

Dr. Wang opened the session by reiterating the Council’s interest in the lack of industry investment in CNS drug development. The NAMHC FAST Working Group, chaired by Drs. Steve Hyman and Steve Paul, found that late-stage expensive failures explained part of the problem, related to how CNS drug trials are designed. The Fast Working Group recommended an experimental approach designed to fail poor targets early, when it is inexpensive, and identify the best targets for further investment. He introduced Jill Heemskerk, Ph.D., Deputy Director, Division of Adult Translational Research, to provide an update on the ongoing work of the FAST trials, which are designed to have a clear target and mechanism, and use measures of engagement that can provide a functional readout of whether the target is associated with something of significance to patients with mental disorders. This determination leads to a go/no-go decision.

Dr. Heemskerk began by drawing the distinction between heart disease, which has seen a dramatic increase in the number of drug mechanisms identified since the 1950s, versus depression and schizophrenia, which have seen almost no change. In the field of neuroscience, we learn little from the standard approach to clinical trials, in which studies are designed around a convenient drug and dose, small sample size, and efficacy as the primary outcome—factors that impractical—of not impossible—to calibrate for mental disorders. As a result, negative results are meaningless and do not tell us whether the dose was too low/too high, the study was underpowered, or the wrong patients were recruited. Typically, a negative result reappears in the form of another grant application to slightly modify design and try again. Moreover, because trials are unpowered for the endpoints being evaluated, frequent type-1 error leads to lack of positive findings in confirmatory studies. In response, NIMH is pushing its clinical trials in the direction of experimental medicine, which aims to understand the underlying mechanisms of disease as well as the intervention. Three steps are involved: (1) show that the drug reaches the target, (2) show that the drug affects the target, and (3) correlate target engagement with a clinical signal. This third proof-of-concept phase meets a high bar for industry in terms of investment. Even absent positive results, we learn that the target is not of interest for that particular condition, so focus can be redirected.

The NAMHC FAST Working Group advises on target selection, drug selection, trial design, and allocation of resources. A subgroup is responsible for each of the contracts. NIMH staff is heavily engaged in all projects. Interactions occur with ad hoc consultants, relevant members of Council, and companies supplying the drug. The Working Group has established criteria for deciding which targets to pursue, and most important, that there be a specific and testable hypothesis. Other selection criteria include the following: availability of a PET ligand to evaluate receptor occupancy; use of functional brain target engagement measures; existence of a target-selective, CNS-penetrant, IND-ready compound; and consideration of RDoC principles where appropriate.

The first trial in the Mood and Anxiety Spectrum contract looks at the role of the kappa opioid receptor in anhedonia using a kappa opioid receptor antagonist provided by Lilly Research Laboratories. Besides meeting the criteria for experimental medicine, the trial was designed with the RDoC approach in mind—meaning, patients with anhedonia are enrolled regardless of their DSM diagnosis. Because novel outcomes are being measured, the team is working with external experts toward gathering supporting data in a way that will be acceptable to the Food and Drug Administration. It is NIMH’s hope that positive findings will spur other drug development interest in the potential therapeutic value of kappa opioid antagonists as well as interest in studies of the mechanisms. It is also hoped that this study will serve as an example of the type of trial NIMH is aiming to support through investigator-initiated grants. To increase the number of targets that are amenable to this approach, investment is needed in biomarkers that can be used to test hypotheses.

Discussion

Dr. Hyman said that although the FAST approach is not really fast, it is smart. In addition to being aligned with RDoC, the kappa opioid study is based on a hypothesis that brain reward and other striatal circuitry is involved in the hedonic state. Target validation is not a moment in time, but rather a process of gaining increasing confidence through a variety of approaches. The study includes measures of this as well as focusing on a condition that patients care about. Nonetheless, compelling targets are lacking for the neuropsychiatric disorders, an area in which the IRP might play a role. As such, this is a major capacity-building exercise as well as research. If new targets are not found, the project could end, but NIMH staff should learn from the experience and use those lessons in future efforts. Susan Amara, Ph.D., NIMH Scientific Director, responded that there is ongoing interest in target development in the IRP. Dr. Tamminga said that the Duniquely suited to do some aspects of drug development and encouraged that there be an intramural scientist associated with each FAST trial. Dr. Wang added that development of PET ligands to study target engagement is a useful role of the IRP.

With regard to capacity building, Dr. Rotheram encouraged diversity in the FAST teams.

Dr. Tamminga said that an important aspect of the FAST effort is that it is a process in which discussions occur at each step along the way, which differs from traditional drug trials. Dr. Simon added that the investigators in this trial appear to be truly in equipoise, which will help to discover the truth. It is important that across the different candidates for study, investigators have agreed to use the common platform of FAST, which is a cultural shift.

Dr. Brent asked how this process would work if the target was not in the brain—for example, some change in family process in a family intervention. Dr. Oquendo clarified by saying that some patients do not want to take a pill, so the intervention will not be pharmacological and other measures of improvement of psychopathology will be needed that are not centered on a compound.

Dr. Linehan expressed support for an approach that deliberately aims to understand the mechanisms of effect, which is an advance in the study of behavioral interventions. She also asked whether there have been big enough samples for the “fail fast” criterion to be valid. Dr. Wang said that going forward there will be discussions about whether NIMH should fund fewer, larger studies versus many smaller studies. Hakon Heimer, M.S., asked whether there could be a separate process to evaluate why compounds that have an effect in animal models do not translate to humans. Dr. Hyman responded that animals can be useful in determining what is evolutionarily preserved in various species and in ascertaining the circuit or behavior or cognitive path that is reasonably preserved. Unfortunately, the field still does not have an animal model of depression.

Dr. Wang closed the session by noting what a culture change the FAST program is for the research community, both for the extramural investigators and the program staff.

Concept Clearance

Anjene Addington, Ph.D., M.P.H., Division of Neuroscience and Basic Behavioral Science, introduced the concept, which is to conduct a project to estimate population prevalence of rare variants as well as phenotypic manifestations associated with neurodevelopmental disorders using a large health network or population-based registry system. The aim is to study the rare variants, especially regions of the genome that have been either duplicated or deleted on certain chromosomes (DNA copy number variants [CNVs]), that consistently have been shown to be risk factors for psychiatric disorders. Initial studies have been small, so most of the CNVs identified were unique to a particular family. As studies have been replicated, the list of CNVs that are highly replicable and recurrent in psychiatric conditions has grown. These CNVs are associated with many phenotypes, such as autism, schizophrenia, and epilepsy. Screening a large sample size would arrive at true population prevalence. Once an individual with the genotype is identified, an in-depth clinical assessment would follow using all of the RDoC domains to assess the impact of the variants on a broad scale.

Discussion

Dr. Barch said that given the small number of individuals who will undergo the extensive phenotyping, measures of brain function and structure should be included because similar phenotypes can have very different underlying neurobiology.

In response to a question from Dr. Robinson about the focus of the proposed project, Dr. Addington said that it is not intended to be a discovery-type initiative, but rather to focus on known variants. Dr. Robinson said that attention must be paid to the source of the variations and whether they ultimately are meaningful.

In response to a question from Dr. Simon about the age range of the sample, Dr. Addington said ideally the sample will include all developmental stages with cross-sectional analysis at different ages. Dr. Carpenter asked whether some of the CNVs might be so large or in different places that a multitude of factors might be affecting phenotype, including behavior and environmental effects, and whether gene dosage effects should be considered. Dr. Addington agreed that some of the CNVs being considered are large and capture many genes, and that complementary studies at the mechanistic level are being considered. The Council voted to approve the concept.

Public Comment

Dr. Wang invited members of the audience to make any comments to the Council.

Mike Byer, of the M3 Collaborative, said his organization focuses on identification and treatment of mental health in primary care. It recently received National Center for Quality Assurance certification to help manage mental health (depression, anxiety, bipolar disorder, post-traumatic stress disorder) in primary care. In primary care, quantitative measures typically are used to manage physical health issues such as blood pressure, cholesterol, but similar quantitative measures are not readily available or used for mental health problem. The M3 Collaborative is calling for greater quantification in mental health care in an effort to reduce the mismanagement of mental health disorders in primary care.

Dr. Wang thanked all who participated in the meeting. He recessed the open session meeting at approximately 2:20 p.m.

Appendix A

Summary of Primary MH Applications Reviewed

January 2014

Category

IRG Recommendation

Scored #

Scored Direct Cost $

Not Scored (NRFC) #

Not Scored (NRFC) Direct Cost $

Other #

Other Direct Cost $

Total #

Total Direct Cost $

Research

499

$589,070,049.00

508

$521,941,709.00

11

$1,337,058.00

1018

$1,112,348,816.00

Research Training

29

$50,253,018.00

7

$9,176,306.00

0

$0.00

36

$59,429,324.00

Career

60

$39,774,744.00

22

$14,642,902.00

1

$0.00

83

$54,417,646.00

Other

0

$0.00

2

$2,498,765.00

0

$0.00

0

$2,498,765.00

Totals

588

$679,097,811.00

539

$548,259,682.00

12

$1,337,058.00

1139

$1,228,694,551.00

Appendix B

Department of Health and Human Services National Institutes of Health National Institute of Mental Health National Advisory Mental Health Council